The role of the Src family kinase Lyn in the immunomodulatory activities of cathelicidin peptide LL-37 on monocytic cells

Abstract

Cathelicidin LL-37 is a multifunctional, immunomodulatory and antimicrobial host-defense peptide of the human immune system. Here, we identified the role of SFKs in mediating the chemokine induction activity of LL-37 in monocytic cells. LL-37 induced SFK phosphorylation; and chemical inhibitors of SFKs suppressed chemokine production in response to LL-37 stimulation. SFKs were required for the downstream activation of AKT, but Ca(2+)-flux and MAPK induction were SFK-independent. Through systematic siRNA knockdown of SFK members, a requirement for Lyn in mediating LL-37 activity was identified. The involvement of Lyn in cathelicidin activities was further confirmed using Lyn-knockout mouse BMDMs. The role of SFKs and Lyn was also demonstrated in the activities of the synthetic cationic IDR peptides, developed as novel, immunomodulatory therapeutics. These findings elucidate the common molecular mechanisms mediating the chemokine induction activity of natural and synthetic cationic peptides in monocytic cells and identify SFKs as a potential target for modulating peptide responses.

Significance of LL-37 on Immunomodulation and Disease Outcome

“…Furthermore, LL-37 induce monocyte [29], fibroblasts [30], epithelial cells [29], and human airway smooth muscle (HASM) cells [31] to secrete IL-8, which further indirectly attracts immune cells, then these cells together with LL-37 against the infection. In addition, other chemokines which have the ability to attract more immunocompetent cells like neutrophils, monocytes, DCs, and T cells, that are released by the cells encounter infections upon treatment with LL-37, for instance, CCL4, CCL20, and C-X-C motif ligand (CXCL) 1 proved to be produced by primary monocytes [32], C-C motif ligand (CCL) 2 released by endothelial cells [33], CCL3 and CCL2 by mast cells [34], and a synergistic increase in CCL20, CXCL1, CXCL8 (IL-8), and CCL2 secretion upon LL-37 exposure to keratinocyte-fibroblast cocultures [35].…”